DE2117572B2 - - Google Patents

Description

[see. Knoevenagel, Ber. 31, 743 (1898)} after this method has so far obtained symmetrical 1,4-dihydropyridines. Unsymmetrical 1,4-dihydropyridines according to the general formula I are not yet known.

The application therefore relates to asymmetrical l ^ -dihydropyridine-S ^ -dicarboxylic acid esters of the general formula I.

HRR ² OOC V / COOR ⁴

in the

R is a phenyl radical, which is replaced by trifluorometäiyl, Halc & sn, carbethoxy, alkyl or alkoxy with} e! is mono-, dä- or trisubstituted up to 2 carbon atoms, means,

R ¹ and R ^{3 are} identical or different and are hydrogen or alkyl having 1 to 2 carbon atoms and

R ² and R ^{4 are} always different from one another and represent a straight-chain or branched, saturated or unsaturated hydrocarbon with up to 6 carbon atoms, it being possible for the saturated, aliphatic hydrocarbon chain to be interrupted by 1 oxygen atom.

It has now been found that the unsymmetrical 1,4-dihydropyridines of the general formula I can be used if you get either

a) Ylidene-jS-ketocarboxylic acid esters of the general Formula Il

COR ¹

RCH = C

(II)

COOR ²

RCH = C

COR ¹

COOR ²

(II)

IO

15th

20th

25th

30th

45

in which

R, R ¹ and R ^{2 have} the abovementioned meaning with enaminocarboxylic acid ester of the general formula III

R ³ -C = CH-COOR ⁴ (III)

NH ₂

in which

R ³ and R ^{4 have} the abovementioned meaning, or

b) if you ylidene-JJ-ketocarboxylic acid ester of general formula II

50

55

60

65

in which

R, R ¹ and R ^{2 have} the abovementioned meaning

sit, with / J-ketocarboxylic acid esters of the general formula IV

R ³ COCH, COOR ⁴

(IV)

in which

R ³ and R ^{4 have} the abovementioned meaning, and ammonia converts, or c) if ylidene-0-ketocarboxylic acid esters of the general formula V are used

COR ³

RCH = C

(V)

COOR ⁴

in which

R, R ³ and R ^{4 have} the abovementioned meaning, with enaminocarboxylic acid ester of the general formula Vl

R ¹ C = CHCOOR ² (VI)

NH ₂

in which

R ¹ and R ^{2 have} the aforementioned meaning, or

d) if ylidene-ji-ketocarboxylic acid ester of the general formula V

COR ³

RCH = C

COOR ⁴

in which

R, R ³ and R ^{4 have} the abovementioned meaning with 0-ketocarboxylic acid esters of the general formula VII

R ¹ COCH ₂ COOR ²

(VII)

in which

R ¹ and R ^{2 have} the abovementioned meaning, and ammonia,

in the presence of water or inert organic solvents.

Surprisingly, the unsymmetrical 1,4-dihydropyridines according to the invention show the general Formula I has a considerably stronger coronary-expanding and antihypertensive effect than that from the prior art Technically known symmetrical 1,4-dihydropyridines.

The following table is an example of some compounds according to the invention have shown that the blood pressure lowering of the asymmetrical ester is marked is above the lowering of blood pressure of the chemically closest symmetrical dihydropyridine ester. At the same time, the compounds of the general formula I according to the invention show a lower toxicity than the well-known symmetrical dihydropyridines. Furthermore, they are the well-known vasodilator The active ingredient is clearly superior to papaverine and is therefore an asset to the pharmaceutical industry.

Table 1

H ₃ CI CH ₃
H

Connection no.

R ² Blood pressure lowering of the blood vessels

> 20 mm Hg tion dose mg / kg Papavep. o. (rat) rin = 1 (Cat)

(Mouse)

1 C ₂ H ₅

(US-PS3441648)

(DT-OS 2005 116)

C ₂ H ₅ CF ₃

3.1

CF ₃

-CH ₂ -CH = CH ₂ -CH ₂ -CH = CH ₂ / V- 10.0

100-300 80

1-10

(Example 4)

C ₂ H ₅

CH, -C = CH

1.0

300-1000 200

(Example 13)

C, H,

-CH, -C = C

1.0

100-300 2000

(Example 15)

-CH (CH ₃ ), -CH ₂ -CH = CH ₂

3.1

The vasodilator effect was measured on the femoral artery of the cat and the blood pressure effect was determined on Goldblatt high pressure rats according to Breuninger. H: method of bloodless Measurement of blood pressure in small animals, Arzneimitteliforschung 6, 222-225 (1965).

With knowledge of the prior art, the advantageous effect was the asymmetrical one according to the invention Dihydropyridines not expected. Rather, it was to be expected that the strength of the

H ₁ CC COO-

'I.

asymmetrical ester lies between the values of the corresponding symmetrical ester.

If ethyl 3-trifluoromethylbenzylideneacetoacetate is used and j3-aminocrotonic acid ester as such starting materials, with both ester groupings once contain the methyl and once the iso-propenyl group, the respective reaction ablawf the Process variants a) to d) are represented by the following formula schemes:

CF ₃

/ Ii CH ₂

HV H ₁ COOC \ I COO-C

■ \ Λ / \

CH, I CH ₃ H

H., C-CO

II, C C O d)

H ₁ CC O

CH + H ₁ C 'CO + NH, II, O

C (H, CII,

COO C COOCH,

CII ₁

(. Il C

COOCH.,

Cl '.

CII C

COOCH ₁

ιι, ι (Nn. cn

COO C

CII ₁

- H ₁ CCO ~ NH, IU) (H, CM,

COO C

CW _x CH, H ₁ COOC \ j COO C

j ■ "cn,

/ 'N ■ - ·. CW, CH,

C I · ',

CII,

C (K) C

CM,

(H ₁

C OOC

CH,

(00 (H ₁

(H ₁ (Il

Il

Cl- '..

(BUT,

CW _x CH ₁

II

The starting materials which can be used according to the invention are already known and can be prepared according to known ones Establish methods. Examples are:

a) Ylidene - ^ - ketocarboxylic acid ester

2'.3'- or 4-methoxybenzylideneacetoacetic acid

ethyl ester. 2'.3'- or 4'-methoxybenzylidene acetoacetic acid methyl ester.

2'-Methoxybenzylidene acetoacetic acid uΓealyl ester. - _{) (} >

2'-methoxyben'ylideneacetoacetic acid prop-

argyl ester. 2'-methoxybenzylidene acetoacetic acid - ^ - methoxy-

ethyl ester, S '^' ^ '- trimethoxybenzylideneacetoacetic acid

ethyl acetate, 2'-methyl-a-benzylidene propionyl acetic acid

methyl ester, 2'3'- or 4'-methylbenzylideneacetoacetic acid

ethyl ester, eo

2'-MethyIbenzylidenacetoacetic acid - ^ - ethoxy-

ethyl ester, 2'-methylbenzylideneacetoacetic acid - /? - propoxy-

ethyl ester, S '^' - Dimethoxy-S'-bromobenzylideneacetoacetic-

ethyl acid ester, 2'3'- or 4'-chloro- / bromo- / fluoro-benzylidene acetoacetic acid ethyl ester.

Methyl 2-fluorobenzylidemcetoacetate. ethyl i'-chlorobenzylidene acetoacetate. Allyl 2-chlorobenzylideneacetoacetate, 2'-chloro -; \ - benzylidene propionyl acetic acid

ethyl ester,
2.3'- or 4'-TriΠuormethylbenzylidenacetcssig ■

ethyl acid ester.
2'Trifluoromethylbenzylideneacetoacetic acid

propyl ester.
2'-Trifluoromethylbenzylidenacetei) acetic acid

isopropyl ester.
2 -Trifluoromethyl-Ä-Benzylidenpropionylessig-

ethyl acid ester,
2'-trifluoromethylbenzylidene acetoacetic acid

propargyl ester,
S'-trifluoromethylbenzylidene acetoacetic acid methyl ester.

b) ^ -Ketocarboxylic acid ester

Ethyl formylacetate, methyl acetoacetate, Ethyl acetoacetate,

Propyl acetoacetate,

Isopropyl acetoacetate, butyl acetoacetate,

Acetoacetic acid ^ «- or ^ -) - methoxyethyl ester,

Acetoacetic acid - ^ «- or /? -) - ethoxyethyl ester,

Acetoacetic acid - ^ - or / i -) - propoxyethyl ester,

Allyl acetoacetate.

Propargyl acetoacetate,

Methyl propionyl acetate.

Ethyl propionylacetate,

Isopropyl acetate,

Ethyl butyrylacetate.

c) enaminocarboxylic acid esters

/ J-aminocrotonic acid methyl ester.

, i-aminocrotonic acid ethyl ester.

^ -Airinocrotonic acid isopropyl ester.

, i-aminocorolonic acid propyl ester.

, • J-aminocrotonic acid allyl ester.

/ i-aminocrotonic acid propargyl ester.

^ -Butyl aminocrotonate.

/ J-aminocrotonic acid- ^ niet hoxyä thy lesler,

:} Aininr> rrnton <; äMrr-: i-älhylälhylrster.

(I-aminocrotonic acid / i-propoxyethyl ester.

^ -Tbutyl aminocrotonate.

^ -Amino - ^ - ethyl acrylate.

As a diluent come water and all inert organic solvent in question. These preferably include alcohols such as methanol. Ethanol or propanol. Ether like dioxane. Diethyl ether. Glacial acetic acid. Pyridine. Dimethylformamide, dimethyl sulfoxide or acetonitrile.

The reaction temperatures can be varied within a relatively wide range. In general one works between about 20 and about 200 ° C. preferably at temperatures of the solvent.

The reaction can be carried out under normal pressure, but also under increased pressure. In general one works at normal pressure.

When carrying out the method according to the invention the substances involved in the reaction are each used in approximately molar amounts. That used Ammonia is expediently added in excess.

As active ingredients according to the invention are mentioned in detail:

1) 2,6-dimethyl-4- (2'-trifluoromethylphenyl) -

1 ^ -dihydropyndin-S.S-dicarboxylic acid 3-methyl ester-5-allyl ester.

2) 2,6-Dimethyl-4- (2'-trifluoromethy! Pheny!) -1 ^ -dihydropyridine-S.S-dicarboxylic acid-S-ethyl ester-5 - /? - methoxyethy ! ester.

3) 2,6-Dimethyl-4- (2'-trifluoromethylphenyl) -l ^ -dihydropyridinO.S-dicarboxylic acid-S-ethyl ester-5-propargy) ester.

4) 2-Methyl-6-ethyI-4- (2'-trifluoromethylphenyl) -i ^ -dihydropyridinO ^ -dicarboxylic acid S - ^ - propoxyethyl ester-5-methyl ester.

5) 2,6-Dimethyl-4- (2'-chlorophenyI) -1, 4-dihydropyridine-S ^ -dicarboxylic acid S-isopropyl ester-5-propargyl ester.

6) 2,6-Dimethyl-4- (2'-ethoxyplienyl) -1, 4-dihydropyridine-S ^ -dicarboxylic acid S-allyl ester-S-propargyl ester.

7) 2,6-Dimethyl-4- (3'-trifluoromethylphenyl) -1 ^ -dihydropyridine-S ^ -dicarboxylic acid O-propargyl ester-5-jJ-methoxyethyl ester.

8) 2,6-Dimethyl-4- (3'-trifluoromethylphenyl) -1 ^ -dihydropyridinO.S-dicarboxylic acid O-ethyl ester-5-allyiester.

9) 2,6-dimethyl-4- (3'-trifliormethylpheny!) -

l ^ -dihydropyridine-J.S-dicarboxylic acid-S-methyl-

ester-5-propargyl ester.
10) 2,6-dimethyl-4- (3'-trifluoromethylphenyl) -

l ^ -dihydropyridinO.i-dicarboxylic acid-S-ethyl-

ester-5- / I-ethoxyethyl ester.

These compounds are substances useful as medicines. They have a broad and varied range pharmacological spectrum of activity.

In particular, the following main effects could be demonstrated in animal experiments:

1) The compounds effect at parenteral. oral and perlingual addition a clear and long-lasting expansion of the coronary vessels. This effect on the coronary vessels is caused by a simultaneous nitrite-like heart-relieving Fffrkt reinforced.

They influence or change the heart metabolism in the sense of saving energy.

2) The excitability of the stimulation and conduction system within the heart is reduced, so that an anti-fibrillation effect which can be demonstrated in therapeutic doses results.

3) The tone of the smooth muscles of the vessels becomes strong under the action of the compounds reduced. This vasospasmolytic effect can take place in the entire vascular system, or more or less isolated in circumscribed vascular areas (such as the central nervous system) manifest.

4) The compounds and may lower the blood pressure of normotensive and hypertensive animals thus be used as antihypertensive agents.

5) The compounds have strong muscle spasmolytic effects on the smooth muscles of the stomach. The intestinal tract, the urogenital tract and the respiratory system become clear.

In indicative studies, the compounds according to the invention in Table 2 and Test results shown in Table 3 can be determined. The coronary effect of Table 2 was on anesthetized, cardiac catheterized dogs tested.

Table 2

Example!

Coronary effect

(Increase in oxygen saturation in%

> 20%)

Dose in mg / kg i.v

2
3
4th
5
6th
7th
8th
10
11
12th

0.05

0.01

0.01

0.005

0.001

0.005

0.05

0.01

5.0

0.05

0.003

0.05

0.01

0.05

0.05

; i

continuation

example

Coronary effect

(Increase in oxygen saturation in%;> 20%)
Dose in mg / kg iv

Table 3 example

0.01
0.05
2-5
2-5

Tox. mouse
Dl. »Mg / kg
po

Blood pressure high pressure RiHIe mg / kg p. O.

> 3000

800

800

200

630

200

> 3000

630

> 3000

> 3000

> 3000

100

2000

1000

> 3000

200

> 3000

3000

3000

I from 10.0

jab 10.0

jab 3.1

Jab 1.0

Jab 3.1

Jab 0.3

Jab 31.5

Jab 1.0

Jab 10.0 j from 0.3 Jab 1.0 Jab Jab 3.1 3.1 J 10.0, J 10.0 from 10.0 J from

The active ingredients can be converted into the customary formulations in a known manner , such as tablets, capsules, coated tablets, pills, granules, syrups, aerosols. Emulsions, suspensions and solutions, using inert, non-toxic pharmaceutically acceptable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90 % by weight of the total mixture, ie in amounts which are sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by extending the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, where, for. B. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.

Examples of auxiliary substances include: water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (ζ. B. peanut / ^ ₀ sesame oil), alcohols (ζ. Β. Ethyl alcohol, glycerine), glycols ( ζ. B. propylene glycol, polyethylene glycol); solid carriers, such as. B. natural stone powder (e.g. kaolins, clays, talc, chalk), synthetic stone powder (e.g. highly dispersed silicic acid, silicates), sugar (e.g. raw sugar, milk sugar and grape sugar); Emulsifiers, such as non-ionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxy

₅₅ äthylcii fatty alcohol ether. Alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, sulfite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.

In the case of oral use, tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, in addition to the carrier substances mentioned. Contain gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous ¹ 'suspensions and / or elixirs intended for oral use, the active ingredients can be mixed with various flavor enhancers or colorings in addition to the abovementioned auxiliaries.

In the case of parenteral use, solutions of the active ingredients can be made using suitable solutions liquid Triigermaterialien are used.

Preparation examples Example 1

After boiling a solution of 11.6 g for 10 hours 2'-Methylbenzylidenacetessigsäureäthylester and 7.1 g, i-aminocrotonic acid allyl ester in 50 ml of ethanol was the 2,6-dimethyl-4- (2'-methylphenyl) -1, 4-dihydropyridine-S.S-dicarboxylic acid O-ate clester-S-allyl ester obtained from melting point 105 ° (petroleum ether / ethyl acetate). Yield 46% of theory.

Example 2

By heating a solution of 11.6 g for 5 hours 2'-Methylbenzylidenacetessigsäureäthylester, 7.0 g of propargyl acetoacetate and 2 ml of conc. ammonia in 50 ml of methanol, the 2,6-dimethyl-4- (2'-

methylphenyl) 1,4-dihydropyridine-3,5-diarboxylic acid 3-ethyl ester-5-proparg \! ester of m.p. 129 '(ethanol / HiO). Yield 54% of theory.

Example 3

After heating 11.1 g of methyl 2'-fluorobenzylideneacetoacetate for 5 hours, 7.1 g acetoacetic acid allyiester and 6 m! conc. Ammonia in 50 m! Methanol the 2,6-Dinieih> l-4- {2'-fluorophenyl) -l, 4-dihydru-

pyridinO.S-dicarboxylic acid S-methyl ester-S-aiiyl ester obtained from m.p. 130 ° (ethanol). Yield 61% of theory.

Example 4

By boiling a solution of 143 g of 2'-TΓiΠuormethylbenzylidenacetessigsäureäthylester and 7.0 g / J-aminocrotonic acid propargyl ester in 50 ml of ethanol, the 2,6-Dimethyl-4- (2'-trifluoromethylphenyl) -1 ^ -dihydropyridine-S ^ - S-ethyl dicarboxylate 5-propargyl ester obtained from melting point 130 ° (methanol). Yield 49% of theory.

Example 5

After 8 hours of heating a solution of 14.9 g of ^ -TriRuorrnethyibenzy'idenacetessigsäureaüylcstcr and 6.5 g of ß-aminocrotonic acid ethyl ester in 50 ml of ethanol, the 2,6-dimethyl-4- (2'-trifluoromethylphenyI) -

1,4-dihydropyridine-3,5-dirarboxylic acid 3-ethyl ester-5-allyl ester of m.p. 128 "(pet / oil ether / vinegar scler). Yield 57% of theory.

Example 6

After heating a solution of 13.6 g of methyl 2'-trifluoromethylbenzylidene acetoacetate for 10 hours.

7.0 g of allyl acetoacetate and 6 ml of conc. ammonia in 60 ml of isopropanol, the 2,6-dimethyl-4- (2'-tri-

fluoromethylprienylj-i / l-clihvdropyridin ^ .i-dicarboxylic acid c-4-mcthvlcster-5-allvlcstcr from fp. 115 (Ethanol). Yield 49% of theory.

Example 7

By boiling a solution of 12.4 g of 2'- ^{Methoxybenzylidcnacctessigsa J} ureäthylstcr, 9.2 g AcetcssiEsaurc-tf-propoxvathylester and 6 ml conc. Ammonhk in 50 ml of ethanol was the 2,6-dimethyl-4- (2'-π "sthoxyphenyl) .l ^ -dihydropyridin-SS-dicarbonsäurc-3-ethyl ester-5 - /? -Propoxyethyl ester of mp. 130 (petroleum ether / Lssigester), yield 41% of theory.

Example 8

By hour IjI: / cn <; in a solution of 13.3 g of allyl 2'-chlorobenzylideneacetoacetate and 6.5 g / f-Aminocrotonsäureäthylcstcr in 50 ml of ethanol the 2,6-dimethyl-4- (2'-chloropnenyl) -l.4-dihydropyridine-S.S-dicarboxylic acid O-ethyl ester-S-allyl ester with a melting point of 115 ° (petroleum ether / ethyl acetate). Yield 40% the theory.

Example 9

After boiling a solution of 15.4 g of ethyl 2 ', 3'.4'-trimethoxybenzylideneacetoacetate for 10 hours.

7.1 g of allyl acetoacetate and 6 ml of conc. ammonia in 40 ml of ethanol was the 2,6-dimethyl-4- (2'.3 ', 4'-trimethoxyphenyl) -1 /i-dihydropyridin^.S-dicarboxylic acid-3-ethylester-5-allylester obtained from m.p. 134-135 ° (ethanol). Yield 58% of theory.

B e i s ρ i e 1 10

After heating a solution of 17.2 g of 3 ', 4'-dimethoxy-5'-bromobenzylideneacetoacetic acid methylate for 10 hours and 7, i g / 3-Äminocrotonsäurealiiyiester in 50 ml of ethanol became the 2.6-Dimethy! -4- (3 ', 4'-dimeth-

oxy-5-bromophenyl) -1 ^ -dihydropyridine ^ .S-dicarbon-5äüre-3-rneihyiester-5-a! ly! esier from mp. 123 to 124 ⁼ (ethanol / water). Yield 62% of theory.

Example 11

After boiling a solution of 11.7 g for 10 hours Methyl 2'-methoxybenzylidene acetoacetate, 7.0 g Propargyl acetoacetate and 6 ml knnz. ammonia in 80 ml of ethanol under reflux, the 2,6-di-

methyl 4- (2'-methoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid, S-propargyl ester, S-methyl ester obtained from mp. 193 to 194 ° C (ethyl acetate / petroleum ether). Yield 49% of theory.

Example 12

By heating a solution of 13.6 g of methyl 2'-trifluoromethylbenzylidene acetoacetate for 8 hours and 7.0 g of propargylic aminocrotonate in 80 ml of ethanol, the 2,6-dimethyl-4- (2'-trifluoromethyl-

phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-propargylesler-5-methyl ester obtained from melting point 111 ° C (Pe- -) trol ether / ethyl acetate). Yield 63% of theory.

Example 13

After boiling a solution of I ^ ) g ι (i 2'-Trifluoromethylbenzylidenacetoessigsäureäthylester, 6.5 g of propargyl acetoacetate and 6 ml of concentrated ammonia in 80 ml of ethanol, the 2,6-dimethyl-4- (2-trifluoroniethylphenyl) -1, 4 -dihydropyridine-3,5-dicaibonic acid-3-propargyl ester-5-ethyl ester of melting point 104 ¹ C r, (ethyl acetate / petroleum ether). Yield 54% of theory.

Example 14

.ιι By heating a solution of 12.bg for 5 hours 2'Chlorhcnzylidenacetessigsäureäthylester, 8.0 g acetic acid - /? - - methoxyethylester and 6 ml conc. Ammonia in 80 ml of ethanol under reflux became 2,6-diniethyl-4- (2'-chlorophenyl) -l, 4-dihydropyridine-3.5-uicai -

:, bonsäure ^ - ^ - methoxyethyl ester-S-ethyl ester of m.p. 107 to 10 8 "C (ethyl acetate / petroleum ether) obtained. Dent 54% of theory.

Example 15

By boiling a solution of 15.0 g of isopropyl S'-trifluoromethylbenzylideneacetoacetate and 7.1 g of allyl aminocrotonate in 80 ml of ethanol, the 2,6-dimethyl-4- (3'-trifluoromethylr, phenyl) -l ^ -dihydropyridine-SS- dicarbonsäureO-isopropyl-5-allyl ester obtained, mp. 99 to 100 ⁰ C (Essigester / petroleum ether). Yield 62% of theory.

Example 16

After boiling a solution of IUg 2'-fluorobenzylideneacetoacetic acid methyl ester for 8 hours. 7.0 g propargyl acetoacetate and 6 ml conc. Ammonia in 100 ml of ethanol, the 2,6-di-. IethyI-4- (2'- i \ fluorophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid 3-propargyl ester-5-methyl ester of mp. 142 ° C (ethanol) obtained. Yield 67% of theory.

Example 17

After heating a solution of 12.6 g of S'-chlorobenzylideneacetoacetate for 8 hours. 7.1 g of acetoacetic acid aüyiesicr and b mi kuiu. Ammonia in 80 mi Ethanol under reflux was the 2,6-dimethyl-4- (3'-chlorophenylJ-l ^ dihydropvridine-S.S-dicarboxylic acid- 3-allyl ester-5-ethyl ester with a melting point of 112 ° C. (ethyl acetate / petroleum ether) was obtained. Yield 57% of theory.

Example 18

After boiling a solution of 12.4 g of ethyl 2'-methoxybenzylidene acetoacetate, 7.0 g, for 10 hours Propargyl acetoacetate and 6 ml of conc. Ammonia in 60 ml of propanol-2 was the 2,6-dimethyl-4- (2'-methoxyphenyl) -l , 4-dihydropyridine-34-dicarboxylic acid 3-propargyl ester-5-ethylsier front fp. 113 to 114 "C (Ethyl acetate / petroleum ether) obtained. Yield 47% of theory.

Example 19

After heating a solution of 15.0 g of T-carboxyethylbenzylideneacetic acid parargyl ester for 8 hours and 6.5 g of ethyl aminocrotonate in 50 ml of ethanol, the 2,6-dimethyl-4- (4'-carboxyethyl-

phenyl obtained) -1 ^ -dihydropyridin-S ^ -dicarboxylic acid-S-propargyl-5-ethyl ester, mp. 110 ⁰ C (ethanol). Yield 55% of theory.

Example 20

After 6 hours of heating a solution of 2,4,5-trimethoxybenzylideneacetoacetic acid, 7.1 g of allyl acetoacetate and 6 ml of alcohol in 100 ml of ethanol, 2,6-dimethymethoxyphenyl) -l, 4-dihydropyridine-3,5-d S-allyl ester get S-melhylester mp. 98 ° "petroleum ether). Yield 53% dei

Claims (1)

21 1
1 in o'er R is a phenyl radical, which is formed by trifluoro COR ¹ in which in which COR ¹ / COOR ² in which 7th 572
2 in which COR ¹ in which in which COR ³ / 1 methyl, halogen, carbethoxy, alkyl or / R, R ¹ and R ^{2 have} the abovementioned meaning R ¹ and R ^{4 have} the abovementioned meaning RCH = C (II) R, R ¹ and R ^{2 have} the abovementioned meaning own, with / J-ketocarboxylic acid esters of R ³ and R ^{4 have} the abovementioned meaning RCH = C (V) R, R ³ and R ^{4 have} the abovementioned meaning R ¹ and R ^{2 have} the aforementioned meaning RCH = C (V)
COOR ⁴ % Patent claims: Alkoxy with 1 to 2 carbon each RCH = C (II) own, with enaminocarboxylic acid ester of own or \ general formula IV own, and ammonia converts, or \ own, with enaminocarboxylic acid ester of I sit, or 1. Unsymmetrical 1,4-Dih> dropyridine-3,5-di- atoms is mono-, di- or tri-substituted. COOR ² general formula III b) Ylidene-0-ketocarboxylic acid ester of the general R ³ COCH ₁ COOR ⁴ (IV) c) ylidene-ß-ketocarboxylic acid ester of the general COOR ⁴ general formula d) ylidene-ß-ketocarboxylic acid ester of the general in which g carboxylic acid ester of the general formula means. my formula Il 5 my Formula Vee my Formula Vee R, R ³ and R ^{4 have} the abovementioned meaning R ^! and R ^{3 are the} same or different and are water R ^J -C = CH-COOR ⁴ (III) R ¹ C = CHCOOR ² (VI) own, with / 3-ketocarboxylic acid esters of MR substance or alkyl of 1 to 2 carbon I. I. general formula VII R ² OOC V / COOR ⁴ atoms mean and NH ₂ NH ₂ R ¹ COCH ₂ COOR ² (VII) W. R ² and R ^{4 are} always different from one another and in which * AA ^(I) a straight or branched chain. IO R ¹ and R ^{2 have} the abovementioned meaning; / N \
R ¹ HR ³ saturated or unsaturated coals own, and ammonia, ρ hydrogen with up to 6 carbon in the presence of water or inert organic % atoms mean, where the saturated. 15th niche solvents S aliphatic hydrocarbon chain interrupted by 1 oxygen atom 3. Medicines containing at least one ver ^y : can be. bond of the general formula I according to 2. Process for making compounds Proverb 1. I. according to the general formula I in claim 1, 20th characterized in that one either a) Yliden-jJ-ketocarboxylic acid ester of the general my formula H The invention relates to asymmetrical 1,4-dihydro 25th pyridine-3,5-dicarboxylic acid ester, several processes to ' their manufacture and their use as medicinal products ;; agents, especially as coronary agents and antihypertensive tensiva. It is already known that the implementation 30th of ethyl benzylidenacetoacetate either with jS-aminocrotonic acid ethyl ester or with acetoacetic acid ^; acid ethyl ester and ammonia, 2,6-dimethyl-4-phenyl- l ^ -dihydropyridinO.S-dicarboxylic acid diethyl ester provides r 35 40 45 50 55 60 h5